July 11, 2014Amyloid diseases, such as Alzheimer’s disease, type 2 diabetes, cataracts, and the spongiform encephalopathies, all share the common trait that proteins aggregate into long fibers which then form plaques. Yet in vitro studies have found that neither the amylin monomer precursors nor the plaques themselves are very toxic. New evidence using two-dimensional infrared (2D IR) spectroscopy has revealed an intermediate structure during the amylin aggregation pathway that may explain toxicity, opening a window for possible interventions, according to a report in the current issue of Biomedical Spectroscopy and Imaging.

“Figuring out how and why amyloid plaques form is exceedingly difficult, because one needs to follow the atomic shapes of the protein molecules as they assemble. Most tools in biology give either shapes or motions, but not both. We have been developing a new spectroscopic tool, called two-dimensional infrared spectroscopy, which can monitor the plaques as they form in a test tube,” said lead investigator Martin T. Zanni, PhD, of the Department of Chemistry at the University of Wisconsin-Madison.

The investigators employed this new technology to study the amyloid protein associated with type 2 diabetes. Isotope labeling was used to measure the secondary structure content of individual residues. By following many 2D IR spectra from one particular region (known as the FGAIL region) over several hours, they were able to visualize the amylin as it progressed from monomers to fibers.

“We learned that, prior to making the plaques, the proteins first assemble into an unexpected and intriguing intermediate and organized structure,” commented Dr. Zanni. The proteins undergo a transition from disordered coil (in the monomer), to ordered β-sheet (in the oligomer) to disordered structure again (in the fiber).

Caption: Schematic of the intermediate structure in the aggregation pathway of amylin. Credit: Zhang, Buchanan, Zanni, Biomedical Spectroscopy and Imaging.

These results help to elucidate the physics of the aggregation process, the chemistry of amyloid inhibitors, and the biology of type 2 diabetes, as well as clarify previously contradictory data.

The authors suggest that differences between species in their capacity to develop type 2 diabetes may be related to the capacity to form these intermediate amylin structures. That may be why humans develop the disease while dogs and rats do not. “I am not encouraging us to begin engineering our DNA to match that of rats, but our findings may help to develop plaque inhibitors or hormone replacement therapies for people suffering from type 2 diabetes, because we know the structure we want to avoid,” says Dr. Zanni. He adds that mutations in the FGAIL region may inhibit fiber formation by interfering with the formation of these intermediates.

Full text of the article is available to credentialed journalists upon request. Contact Esther Mateike, IOS Press, at +31 20 688 3355 or e.mateike@iospress.nl. Journalists wishing to interview the authors should contact Martin Zanni at 608-262-4783 or zanni@chem.wisc.edu.

The study was supported by the National Institutes of Health (NIH) Grant DK79895 and the National Science Foundation (NSF) through a Graduate Research Fellowship Program Grant DGE-0718123.

ABOUT BIOMEDICAL SPECTROSCOPY AND IMAGING (BSI)Biomedical Spectroscopy and Imaging is dedicated to providing a single forum for experts in spectroscopy and imaging as applied to biomedical problems, and also for life scientists who use these powerful methods for advancing their research work. BSI aims to promote communication, understanding and synergy across the diverse disciplines that rely on spectroscopy and imaging. It also encourages the submission of articles describing development of new devices and technologies, based on spectroscopy and imaging methods, for application in diverse areas including medicine, biomedical science, biomaterials science, environmental science, pharmaceutical science, proteomics, genomics, metabolomics, microbiology, biotechnology, genetic engineering, nanotechnology, etc. www.iospress.com/journal/biomedical-spectroscopy-and-imaging

ABOUT IOS PRESSCommencing its publishing activities in 1987, IOS Press (www.iospress.nl) serves the information needs of scientific and medical communities worldwide. IOS Press now (co-)publishes approximately 100 international journals and about 80 new books each year on subjects ranging from computer sciences and mathematics to medicine and the natural sciences.

All journals are available electronically and an ebook platform was launched in 2005.

Headquartered in Amsterdam with satellite offices in the USA, Germany, India and China, IOS Press has established several strategic co-publishing initiatives. Notable acquisitions included Delft University Press in 2005 and Millpress Science Publishers in 2008.

Our (e)Books and (e)Journals

IOS Press serves the information needs of scientific and medical communities worldwide. See what's new and browse our books and journals to learn more.